The role of MAP kinase in TPA-mediated cell cycle arrest of human breast cancer cells.
In MCF7 breast cancer cells, mitogen-activated protein (MAP) kinase (i.e. Erk-1/2) is activated by the mitogen insulin, but also by the growth inhibiting agent TPA, though with very different kinetics. Insulin induces a relatively transient activation of Erk2 (<15 min), whereas TPA is able to induce a prolonged activation of Erk2 (>6 h). Expression of immediate-early genes of the c-fos and c-jun families, whose transcription and activation are regulated by MAP kinases, is differentially induced by insulin and TPA. Whereas insulin stimulates prolonged induction of c-jun, but not of junB mRNA, resulting in c-jun expression during the entire G1 period, the growth inhibitor TPA induces junB much longer than c-jun. Inhibition of the Erk2 pathway by PD98059, specific for the upstream MAP kinase kinase (MEK1), abolishes TPA-stimulated junB but not insulin-induced c-jun. In agreement with this, insulin readily stimulates Jun kinase (JNK), whereas TPA does not. Furthermore, insulin-induced pRB hyperphosphorylation at the G1-S transition and S-phase entry is insensitive to MAP kinase inhibition by PD98059. On the other hand, PD98059 reverts the inhibitory effect of TPA on cell cycle entry as well as on pRB hyperphosphorylation, indicating that Erk effectors function as inhibitors of proliferation in MCF7 cells.
Alblas
J
J
Laboratory for Physiological Chemistry, University Utrecht, Stratenum, The Netherlands.
Slager-Davidov
R
R
Steenbergh
P H
PH
Sussenbach
J S
JS
van der Burg
B
B
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007328:Insulin; D016755:Proto-Oncogene Proteins c-jun; D016160:Retinoblastoma Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one